Injection Of Mesenchymal Stem Cells Research Articles

System proteinase/inhibitors in the pathogenesis of experimental kidney tuberculosis

BACKGROUND: Damage to the kidney parenchyma of various origins is associated with the accumulation of extracellular matrix proteins, the regulation of which involves the matrix metalloproteinase/inhibitor system. AIM: To evaluate the pathogenetic role of the proteinase/blood inhibitor system in experimental renal tuberculosis. MATERIAL AND METHODS: When modeling the process, a clinical strain 5582 of the Beijing genotype with multidrug resistance of mycobacteria was used. The study was conducted on 20 rabbits, divided into three groups: the first (n=6) included infected untreated animals; in the second (n=7) and third (n=7) anti-tuberculosis therapy was administered orally for 18.5 weeks; in the third, treatment was carried out in combination with a single injection of autologous mesenchymal stem cells into the ear vein. Blood levels of matrix metalloproteinases-1 and -9, tissue inhibitor of metalloproteinases-1, cystatin C and neutrophil elastase were determined. Morphological changes in the kidney parenchyma at the end of the experiment were assessed using 26 indicators, including tubulointerstitial and vascular changes. The median and interquartile ranges were calculated, the Kruskal–Wallis test, analysis of covariance, and the projective classification method were used. RESULTS: The progression of kidney tuberculosis was accompanied by a significant increase in the level of neutrophil elastase by 1.9 times, matrix metalloproteinase-9 by 2.2 times, and cystatin C by 1.5 times compared to the initial level. The treatment carried out in the second and third groups contributed to the normalization of these indicators. The concentrations of matrix metalloproteinase-1 and tissue inhibitor of metalloproteinase-1 in all three groups did not change relative to the baseline level. Covariance analysis showed that in the pathogenesis of renal tuberculosis changes in matrix metalloproteinase-1 (p=0.003), matrix metalloproteinase-9 (p=0.002), tissue inhibitor of metalloproteinases-1 (p=0.01) and cystatin C (p=0.0001) were primarily associated with vascular changes, found in all study groups. A linear combination containing three morphological characteristics allowed us to identify differences between the three groups with 90% accuracy. CONCLUSION: Renal tuberculosis, caused by a multidrug-resistant pathogen, is characterized by an imbalance in the proteinase/inhibitor system and impaired renal function, the degree of which is associated with the morphological characteristics of vascular and tubulointerstitial changes.

Cytokine Receptor-like Factor 1 (CRLF1) and Its Role in Osteochondral Repair.

Since cytokine receptor-like factor 1 (CRLF1) has been implicated in tissue regeneration, we hypothesized that CRLF1 released by mesenchymal stem cells can promote the repair of osteochondral defects. The degree of a femoral osteochondral defect repair in rabbits after intra-articular injections of bone marrow-derived mesenchymal stem cells (BMSCs) that were transduced with empty adeno-associated virus (AAV) or AAV containing CRLF1 was determined by morphological, histological, and micro computer tomography (CT) analyses. The effects of CRLF1 on chondrogenic differentiation of BMSCs or catabolic events of interleukin-1beta-treated chondrocyte cell line TC28a2 were determined by alcian blue staining, gene expression levels of cartilage and catabolic marker genes using real-time PCR analysis, and immunoblot analysis of Smad2/3 and STAT3 signaling. Intra-articular injections of BMSCs overexpressing CRLF1 markedly improved repair of a rabbit femoral osteochondral defect. Overexpression of CRLF1 in BMSCs resulted in the release of a homodimeric CRLF1 complex that stimulated chondrogenic differentiation of BMSCs via enhancing Smad2/3 signaling, whereas the suppression of CRLF1 expression inhibited chondrogenic differentiation. In addition, CRLF1 inhibited catabolic events in TC28a2 cells cultured in an inflammatory environment, while a heterodimeric complex of CRLF1 and cardiotrophin-like Cytokine (CLC) stimulated catabolic events via STAT3 activation. A homodimeric CRLF1 complex released by BMSCs enhanced the repair of osteochondral defects via the inhibition of catabolic events in chondrocytes and the stimulation of chondrogenic differentiation of precursor cells.

Toll-like receptor activation regulates the paracrine effect of adipose-derived mesenchymal stem cells on reversing osteoarthritic phenotype of chondrocytes.

The therapeutic efficacy of intra-articular mesenchymal stem cells (MSCs) injection for patients with osteoarthritis (OA) currently exhibits inconsistency, and the underlying mechanism remains elusive. It has been postulated that the immunomodulatory properties and paracrine activity of MSCs might be influenced by the inflammatory micro-environment within osteoarthritic joints, potentially contributing to this observed inconsistency. Adipose-derived MSCs (ADSCs) were isolated from SD rats and pre-treated with Toll-like receptor 3 (TLR3) agonist Poly I:C or Toll-like receptor 4 (TLR4) agonist LPS. The pre-treated ADSCs were then co-cultured with IL-1β-induced osteoarthritic chondrocytes using a Transwell system to analyze the paracrine effect of ADSCs on reversing the osteoarthritic phenotype of chondrocytes. RT-PCR and Western blot analysis revealed that Poly I:C and LPS pre-treatments up-regulated the expression of IL-10 and IL-6 in ADSCs, respectively. Furthermore, only Poly I:C-preconditioned ADSCs significantly promoted proliferation while inhibiting apoptosis in IL-1β-treated chondrocytes. Additionally, Poly I:C-preconditioned ADSCs downregulated MMP13 expression while upregulating aggrecan and collagen II expression levels in IL-1β-treated chondrocytes. TLR3 activation polarizes ADSCs into an immunomodulatory phenotype distinct from TLR4 activation, exerting differential effects on reversing the osteoarthritic phenotype of chondrocytes; thus indicating that MSCs' paracrine effect regulated by TLRs signaling impacts the efficacy of intra-articular MSCs injection.

Traitement des fistules anales réfractaires à l’Infliximab au cours de la maladie de Crohn : Mise au point

Treatment of complex perianal fistulas in Crohn's disease remains a challenge especially after the failure of Infliximab. Update on the different therapeutic alternatives for anal fistula in Crohn's disease after failure of Infliximab. A research in the medical literature on PubMed and Google Scholar was carried out. We included cohort studies, reviews and randomized double-blinded therapeutic trials. Case reports and fundamental research studies have been excluded. Anti-TNF therapy, notably Infliximab remain the therapeutic option of choice. Since Infliximab efficacy has been estimated at 60%, with a significant loss-of response rate, new therapeutic strategies have been evaluated and may offer new opportunities for the management of anal fistulas: for example, Ustekinumab could be effective after failure of anti-TNF therapy, although further studies are required. Recent guidelines suggest that injection of mesenchymal stem cells is an effective and safe treatment for complex fistulas. Other surgical options have been proposed, such as endorectal advancement flap, fibrin glue injection, anal fistula plug and ligation of the intersphincteric fistula tract, but all with limited and debatable efficacy. Given the failure rate of all these options, new strategies are currently being evaluated. Anal fistulas in Crohn's disease are a real therapeutic challenge. New medical and surgical therapies are currently being evaluated, with promising results.

Intramuscular injection of mesenchymal stem cells augments basal muscle protein synthesis after bouts of resistance exercise in male mice.

Skeletal muscle mass is critical for activities of daily living. Resistance training maintains or increases muscle mass, and various strategies maximize the training adaptation. Mesenchymal stem cells (MSCs) are multipotent cells with differential potency in skeletal muscle cells and the capacity to secrete growth factors. However, little is known regarding the effect of intramuscular injection of MSCs on basal muscle protein synthesis and catabolic systems after resistance training. Here, we measured changes in basal muscle protein synthesis, the ubiquitin-proteasome system, and autophagy-lysosome system-related factors after bouts of resistance exercise by intramuscular injection of MSCs. Mice performed three bouts of resistance exercise (each consisting of 50 maximal isometric contractions elicited by electrical stimulation) on the right gastrocnemius muscle every 48 h, and immediately after the first bout, mice were intramuscularly injected with either MSCs (2.0 × 106 cells) labeled with green fluorescence protein (GFP) or vehicle only placebo. Seventy-two hours after the third exercise bout, GFP was detected only in the muscle injected with MSCs with concomitant elevation of muscle protein synthesis. The injection of MSCs also increased protein ubiquitination. These results suggest that the intramuscular injection of MSCs augmented muscle protein turnover at the basal state after consecutive resistance exercise.

Mesenchymal stem cells alleviate mouse liver fibrosis by inhibiting pathogenic function of intrahepatic B cells.

The immunomodulatory characteristics of mesenchymal stem cells (MSCs) make them a promising therapeutic approach for liver fibrosis (LF). Here, we postulated that MSCs could potentially suppress the pro-fibrotic activity of intrahepatic B cells, thereby inhibiting LF progression. Administration of MSCs significantly ameliorated LF as indicated by reduced myofibroblast activation, collagen deposition, and inflammation. The treatment efficacy of MSCs can be attributed to decreased infiltration, activation, and pro-inflammatory cytokine production of intrahepatic B cells. Single-cell RNA sequencing revealed a distinct intrahepatic B cell atlas, and a subtype of naive B cells (B-II) was identified, which were markedly abundant in fibrotic liver, displaying mature features with elevated expression of several proliferative and inflammatory genes. Transcriptional profiling of total B cells revealed that intrahepatic B cells displayed activation, proliferation, and pro-inflammatory gene profile during LF. Fibrosis was attenuated in mice ablated with B cells (μMT) or in vivo treatment with anti-CD20. Moreover, fibrosis was recapitulated in μMT after adoptive transfer of B cells, which in turn could be rescued by MSC injection, validating the pathogenic function of B cells and the efficacy of MSCs on B cell-promoted LF progression. Mechanistically, MSCs could inhibit the proliferation and cytokine production of intrahepatic B cells through exosomes, regulating the Mitogen-activated protein kinase and Nuclear factor kappa B signaling pathways. Intrahepatic B cells serve as a target of MSCs, play an important role in the process of MSC-induced amelioration of LF, and may provide new clues for revealing the novel mechanisms of MSC action.

Exosomes derived from MSC as drug system in osteoarthritis therapy.

Osteoarthritis (OA) is the most common degenerative disease of the joint with irreversible cartilage damage as the main pathological feature. With the development of regenerative medicine, mesenchymal stem cells (MSCs) have been found to have strong therapeutic potential. However, intraarticular MSCs injection therapy is limited by economic costs and ethics. Exosomes derived from MSC (MSC-Exos), as the important intercellular communication mode of MSCs, contain nucleic acid, proteins, lipids, microRNAs, and other biologically active substances. With excellent editability and specificity, MSC-Exos function as a targeted delivery system for OA treatment, modulating immunity, inhibiting apoptosis, and promoting regeneration. This article reviews the mechanism of action of MSC-Exos in the treatment of osteoarthritis, the current research status of the preparation of MSC-Exos and its application of drug delivery in OA therapy.

Evaluation of the efficacy of mesenchymal stem cells derived conditioned medium in the treatment of striae distensae: a double blind randomized clinical trial

BackgroundStriae distensae is a disfiguring atrophic skin condition that impairs the body’s aesthetic image. Despite the variety of conducted studies, there is controversy regarding the best modalities. Human mesenchymal stem cells are considered a rich source for scar treatment. Skin needling is among the most efficient and safe aesthetic and therapeutic devices. This study aimed to evaluate the efficacy of the combination of needling and intradermal injection of mesenchymal stem cells compared to skin needling alone for treating striae distensae.MethodThis study was a randomized, double-blind clinical trial involving 10 women aged 18–60. Each striae lesion was divided into two parts, with one side receiving needling and intradermal injection of conditioned medium, while the other side received needling and intradermal injection of normal saline. This treatment was administered in three sessions with three-week intervals. Patients were evaluated before the first intervention and three months after the final session. Three months after the completion of the intervention, patients’ lesions were evaluated using biometric criteria, physician evaluation, and patient self-assessment.ResultsThe results demonstrated a significant improvement in dermal and complete thickness and skin density in patients treated with microneedling. All skin ultrasound parameters improved significantly in patients receiving the combination of needling and conditioned medium. When comparing the two groups, significantly higher physician and patient satisfaction was observed in the combination group. However, the comparison of biometric indices improvement wasn’t significant between these groups.ConclusionThe combination of human mesenchymal stem cells with microneedling could be considered a novel effective option for stretch marks.

Mesenchymal Stem Cells Attenuates Hirschsprung diseases - Associated Enterocolitis by Reducing M1 Macrophages Infiltration via COX-2 Dependent Mechanism

Objective and designHirschsprung disease-associated enterocolitis (HAEC) is a common life-threatening complication of Hirschsprung disease (HSCR). We aimed to investigate the effectiveness, long-term safety and the underlying mechanisms of Mesenchymal stem cells (MSCs) based therapy for HAEC. Material or subjectsSpecimens from HSCR and HAEC patients were used to assess the inflammatory condition. Ednrb knock-out mice was used as HAEC model. MSCs was intraperitoneally transplanted into HAEC mice. The therapy effects, long-term outcome, safety and toxicity and the mechanism of MSCs on the treatment of HAEC were explored in vivo and in vitro. ResultsIntestinal M1 macrophages infiltration and severe inflammation condition were observed in HAEC. After the injection of MSCs, HAEC mice showed significant amelioration of the inflammatory injury and inhibition of M1 macrophages infiltration. The expression levels of pro-inflammatory cytokines (TNF-α and IFN-γ) were decreased and anti-inflammatory cytokines (IL-10 and TGF-β) were increased. In addition, we found that effective MSCs homing to the inflamed colon tissue occurred without long-term toxicity response. However, COX-2 inhibitor could diminish the therapeutic effects of MSCs. Using MSCs and macrophages co-culture system, we identified that MSCs could alleviate HAEC by inhibiting M1 macrophages activation through COX-2-dependent MAPK/ERK signaling pathway. ConclusionsMSCs ameliorate HAEC by reducing M1 macrophages polarization via COX-2 mediated MAPK/ERK signaling pathway, thus providing novel insights and potentially promising strategy for the treatment or prevention of HAEC.

Possible therapeutic effect of combined platelet-rich plasma and stem cells on induced knee osteoarthritis in adult male albino rat: histological and immunohistochemical study

Osteoarthritis (OA) is a degenerative joint disease that results from breakdown of joint cartilage and underlying bone. It is the most common form of arthritis among elderly individuals. The present study aimed to investigate the effect of intra‑articular injection of platelet-rich plasma (PRP) and bone marrow mesenchymal stem cells (BMSCs), both in combination and separately in the treatment of monoiodoacetate (MIA) induced OA in rats. Seventy adult male albino rats were randomly divided into seven groups, 10 rats in each (control, sham control, OA-induced, PRP, BMSCs, PRP+BMSCs and recovery). Histological examination was done using haematoxylin and eosin, alcian blue and Masson’s trichrome stains. Immunohistochemical staining for collagen type II antigen and proliferating cell nuclear antigen (PCNA) was carried out. Measurements of serum interleukin 6 (IL-6) was performed using ELISA. Expression of ACAN gene was done using real-time polymerase chain reaction (PCR) and histomorphometric measurements were analyzed. Radiographs were acquired from the knee joint. Light microscopic examination of articular cartilage (AC) from OA-induced group showed disorganization of chondrocytes, loss of zonation, pyknotic nuclei, empty lacunae and absent tidemark. There was a significant decrease in AC thickness, chondrocytes count, optical density of collagen and proteoglycan content, area percent of collagen II in the matrix in OA group compared to control and sham groups. These degenerative histomorphological alterations were associated with significant increase in serum IL-6 and decrease in ACAN gene expression. Radiographs showed narrowing of joint space and subchondral sclerosis. Intraarticular injection of PRP, BMSCs and PRP+BMSCs improved the previously mentioned alterations. Concomitant administration of PRP+BMSCs showed better effect than using PRP and BMSCs alone. In conclusion, PRP potentiated the effects of BMSCs on the repair of MIA-induced AC damage in rats. Injection of combination of PRP with BMSCs could be considered as a promising therapy for OA in patients.

Comparing the effect of intravenous versus intracranial grafting of mesenchymal stem cells against parkinsonism in a rat model: Behavioral, biochemical, pathological and immunohistochemical studies.

Parkinson's disease (PD) is one of the most common neurodegenerative diseases worldwide. Currently applied therapeutic protocols are limited to improve the motor functions of patients. Therefore, seeking alternative regimes with better therapeutic impact is crucial. This study aims to validate the therapeutic impact of mesenchymal stem cell injection using two delivery methods, intracranial administration and intravenous administration, on rotenone (ROT)-induced PD model in rats. Our work included behavioral, biochemical, histological, and molecular investigations. Open field test (OFT) and rotarod tests were applied. Important oxidative stress, antioxidant and proinflammatory markers were monitored. Substantia Nigra and Striatum tissues were examined histologically and the molecular expression of DOPA decarboxylase, Tyrosine hydroxylase, and α-synuclein in neurons in these tissues were investigated. Our results showed that MSC grafting improved motor and memory impairments and oxidative stress status that were observed after ROT administration. Additionally, BM-MSCs application restored SOD and CAT activities and the levels of DA, L-Dopa, IL6, IL1β, and TNFα. Moreover, MSC grafting overwhelmed the pathological changes induced by ROT and normalized the expression of Tyrosine hydroxylase, DOPA decarboxylase, and α-synuclein towards the control values in the Nigral and Striatal tissues of male rats. Conclusively, both administration routes improved motor function, protection of the nigrostriatal system, and improved striatal dopamine release. The observed beneficial effect of applying MSCs suggests potential benefits in clinical applications. No significant differences in the outcomes of the treatment would favor a certain way of MSC application over the other. However, the intravenous delivery method seems to be safer and more feasible compared to the intrastriatal method.

Intrathecal injection of human placental mesenchymal stem cells derived exosomes significantly improves functional recovery in spinal cord injured rats.

Spinal cord injury (SCI) due to lack of restoration of damaged neuronal cells is associated with sensorimotor impairment. This study was focused on using the human placental mesenchymal stem cells- exosome (HPMSCs- Exosomes) in an animal model of severe SCI under myelogram procedure. Intrathecal injection of exosomes was performed in the acute phase of SCI in female rats. The improved functional recovery of the animals was followed for 6 weeks in control (saline, n = 6) and HPMSCs- EXO (HPMSCs-Exosomes, n = 6) groups. Pathological changes and glial scar size were evaluated. The Immunohistochemistry (IHC) of GFAP and NF200 factors as well as the apoptosis assay was investigated in the tissue samples from the injury site. The results demonstrated that HPMSCs-exosomes can improve motor function by attenuating apoptosis of neurons at the injury site, decreasing GFAP expression and increasing NF200 in the HPMSCs-EXO group. Also, HPMSCs-exosomes by preventing the formation of cavities causes preservation of tissue in SCI rats. These findings demonstrate the effectiveness of HPMSC-Exosomes as a therapeutic method to improve functional recovery, reduce pathological changes associated with injury, and prevent chronicity after SCI. The neuroprotective and anti-apoptotic potential of HPMSCs- Exosomes may be a promising therapeutic approach for SCI. Another result was the importance of intrathecal injection of exosomes in the acute phase, which accelerated the healing process. Furthermore, the myelogram can be a feasible and suitable method to confirm the accuracy of intrathecal injection and examine the subarachnoid space in the laboratory animals.

P933 Closing the internal opening with a rectal advancement flap increases the effectiveness of mesenchymal stem cell (MSC) injection in the treatment of complex Crohn's disease anal fistulas

Abstract Background The injection of MSCs into complex anoperineal fistulas of Crohn's disease gives a combined clinical and radiological remission of between 35 and 50% at 12 months. In our department, surgical closure is now done by rectal advancement flap (and no longer with simple stitches) in order to minimize the passage of stools and contamination of the fistula tract. The aim of this study was to compare the remission rate and the quality of life between patients treated with MSC injection using simple stitches versus a rectal flap to close the internal opening. Methods This single-center prospective study included all our consecutive patients who had a MSC injection. The first patients of the series who had closure of the internal opening(s) with stitches (2020- 2022) were compared with those who had a flap (2022-2023). Complete clinical remission was defined by complete closure of the external opening(s) without pain or discharge, and complete radiological remission by a Magnifi-CD score equal to 0 (Hindryckx P, et al. Gastroenterology 2019). Quality of Life was assessed by the Crohn's Anal Fistula Quality of Life scale (CAF-QoL) (Adegbola SO, et al. Gut 2021). Results We included 68 patients (50% women, mean age: 38 ± 13.8 years). The first 42 had stitches and the following 20 had an advancement flap (6 patients had no procedure due to an anal stenosis). The median follow-up was 12 months [6-24]. The overall complete clinical remission was 66.7% at M12: 51.1% [35.5-66.8] in the "stitches" group versus 87.5% [69.7-100.0] in the "flap" group (p = 0.005) (Figure). The difference was noticed early from M1. The mean overall Magnifi-CD MRI score decreased from 15.5 ± 4.7 to 6.5 ± 7.1 at M12 (p < 0.001) with no difference between the 2 groups. However, more patients in the flap group had a Magnifi-CD score of 0: 62.5% versus 38.2%. The CAF-QoL quality of life score improved from 51.3 ± 24.7 to 21.2 ± 20.8 at M12 (p < 0.001) with no significant difference between the 2 groups. The duration of the procedure was longer on average by 19 ± 7 minutes in the "flap" group. There was no difference in the anal incontinence score between the 2 groups. In logistic regression, the advancement flap was significantly associated with complete clinical remission (p = 0.007, HR (95% CI): 2.3 [1.3-4.3]). Conclusion Closing the internal opening with a rectal advancement flap improves the effectiveness of MSC injections with a complete clinical and radiological remission rate of 87.5% and 62.5% respectively, without consequences on anal continence.

A systematic review of clinical efficacy and safety of cell-based therapies in Alzheimer's disease.

This study aspires to estimate the efficacy and safety of cell-based treatments in AD. Observing the Joanna Briggs Institute (JBI) methods and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, a systematic search was accomplished in PubMed, Medical Literature Analysis and Retrieval System Online (Medline, via Ovid), Embase; Cochrane, and Cumulative Index of Nursing and Allied Health Literature - CINAHL (via EBSCO) databases up to June 2023. The relevant clinical studies in which cell-based therapies were utilized to manage AD were included. The risk of bias was evaluated using the JBI checklists, based on the study designs. Out of 1,014 screened records, a total of five studies with 70 individuals (including 59 patients receiving stem cells and 11 placebo controls) were included. In all these studies, despite the discrepancy in the origin of stem cells, cell density, and transplant site, safety goals were obtained. The intracerebroventricular injection of adipose-derived stromal vascular fraction (ADSVF) and umbilical cord-derived mesenchymal stem cells (UC-MSCs), the intravenous injection of Lomecel-B, and the bilateral hippocampi and right precuneus injection of UC-MSCs are not linked to any significant safety concerns, according to the five included studies. Studies also revealed improvements in biomarkers and clinical outcomes as a secondary outcome. Three studies had no control groups and there are concerns regarding the similarity of the groups in others. Also, there is considerable risk of bias regarding the outcome assessment scales. Cell-based therapies are well tolerated by AD patients, which emphasizes the need for further, carefully planned randomized studies to reach evidence-based clinical recommendations in this respect.

Protective effect of bone marrow mesenchymal stem cells on the survival zone of the perforator flaps in rats.

Perforator flaps have recently been used in the field of plastic surgery. Skin defects can be reconstructed to reach functional and cosmetic goals. With the development of reconstructive approaches, utilizing stem cells is a hopeful approach to enhance wound healing and tissue recovery. In this study, we assessed the effect of bone marrow mesenchymal stem cells on the perforator flap's survival in rats. Perforator flaps (2.5 × 11 cm) were transplanted into rats and focused on the thoracodorsal, intercostal, and deep circumflex arteries, which were randomly divided into three groups: control, saline, and bone marrow mesenchymal stem cells (7 × 106 ml). Seven days after the surgery, tissue edema, inflammation, and discharge were observed and photographed. Histological analyses were performed to determine flap survival. Hematoxylin and eosin staining was performed to assess levels of microvascular density determined in skin flaps. Rats in the bone marrow mesenchymal stem cells group exhibited higher average flap survival area, and higher microvascular density levels at the dynamical regions of the flaps compared with the other two groups. Subdermal injection of bone marrow mesenchymal stem cells significantly increased ischemic perforator flap survival due to stimulated neovascularization in rats. Our findings suggest the potential usefulness of bone marrow mesenchymal stem cells in preventing skin flap perforator tissue necrosis.

Ultrasound-Targeted Microbubble Destruction Increases BBB Permeability and Promotes Stem Cell-Induced Regeneration of Stroke by Downregulating MMP8.

The objective of this study was to evaluate the feasibility, safety, and effectiveness of intravenous stem cell delivery utilizing ultrasound-targeted microbubble destruction (UTMD) in a rat model of middle cerebral artery occlusion (MCAO), while investigating the underlying mechanisms. Acute cerebral infarction (ACI) was induced surgically in adult rats to create the MCAO rat model. Intravenous injection of SonoVue microbubbles and bone marrow-derived mesenchymal stem cells (BMSC) was performed concurrently, with or without ultrasound targeting the stroke. The animals were divided into four groups: sham-operated group, ACI-MCAO rats treated with phosphate-buffered saline (ACI+PBS), rats receiving intravenous delivery of BMSC expressing green fluorescent protein (GFP-BMSC; ACI+BMSC), and rats receiving intravenous GFP-BMSC with simultaneous UTMD exposure (ACI+BMSC+UTMD). The efficacy of the treatments was assessed by evaluating the animals' neurological function using the Longa score and examining histopathological changes such as cerebral infarct volume, cerebral edema, and cell apoptosis. A rat cytokine array was utilized to identify the potential cytokines that may be responsible for the therapeutic effect of UTMD-mediated BMSC treatment. Optimal UTMD parameters resulted in an increase in blood-brain barrier (BBB) permeability after 30 min, which returned to baseline 72 h later without causing any residual injury. UTMD application significantly increased the homing of intravenously delivered BMSC, resulting in a 2.2-fold increase in GFP-BMSC cell count on day 3 and a 2.6-fold increase on day 7 compared with intravenous delivery alone. This effect persisted for up to 6 weeks after injection. Intravenous BMSC delivery significantly reduced the volume of cerebral infarct and decreased cerebral edema, leading to a lower Longa score. Furthermore, this effect was further enhanced by UTMD. Acute cerebral infarction induced by MCAO led to elevated matrix metalloproteinase 8 (MMP8) levels in the cerebrospinal fluid, which were significantly reduced following UTMD-mediated BMSC treatment. Ultrasound-targeted microbubble destruction facilitates the migration and homing of BMSC into the brain, possibly by transiently increasing blood-brain barrier (BBB) permeability, thereby improving therapeutic outcomes in an ACI rat model. The observed effect may be partly attributed to modulation of MMP8 levels.Advances in knowledge: UTMD-mediated intravenously delivered BMSC transplantation led to a significant increase in cell homing and reduction of MMP8 levels, resulting in increased therapeutic effect in an acute ischemic cerebral infarction model.

Improvement of endometrial thickness and in vitro fertilization outcomes in patients with Asherman's refractory endometrium using autologous mesenchymal stem cells from the stromal vascular fraction.

Patients with Asherman's Syndrome (AS) and an endometrial thickness (EMT) less than 7 mm are infertile women with suboptimal endometrium due to uterine scarring or endometrial atrophy. This study aimed to examine the effect of intrauterine injections of adipose-derived mesenchymal stem cells (ADMSC) from the Stromal Vascular Fraction (SVF) of adipose tissue on EMT and in vitro fertilization (IVF) outcomes: which are improvements in EMT and pregnancy rates. This double-arm retrospective study included 41 AS patients with hysteroscopic adhesiolysis. Twenty-one patients with AS refractory endometrium (Group 2) were given ADMSC to improve EMT, and 20 non-treated, age-matched patients served as controls (Group 1). For Group 2, SVF was isolated from 15 ml of adipose tissue and transmyometrial injected into the patient's uterine cavity. For all patients, EMT was examined using ultrasound before embryo transfer. In Group 2, after ADMSC treatment, EMT significantly improved (3.2 ± 1.8 mm, P<0.001). Afterward, three patients spontaneously became pregnant, and eighteen underwent frozen embryo transfer. A significant increase in implantation (66.7% vs. 4.8%, P = 0.002) and live birth rates (0.0% vs. 47.6%, P = 0.001) were recorded. No significant difference was observed in EMT, cycle implantation, or clinical pregnancy between the two groups, but the live birth rate in Group 2 after ADMSC treatment was higher than in Group 1. The results demonstrate that autologous intrauterine ADMSC injection can improve EMT, implantation, and pregnancy rates in AS patients with refractory endometrium. This research underscores the life-changing potential of autologous ADMSC treatment for patients with refractory endometrium, providing a promising avenue for future treatments.

Clinical efficacy of mesenchymal stem cells and platelet-rich plasma in the therapy of osteoarthritis: a meta-analysis.

Intra-articular administration of mesenchymal stem cells (MSCs) presents a novel methodology for managing osteoarthritis, but there is still no definite evidence of its efficacy. To assess the comparative effectiveness of MSCs and platelet-rich plasma (PRP) for managing osteoarthritis by reviewing the literature and using meta-analysis. Randomized controlled trials and cohort studies comparing MSCs and PRP for managing osteoarthritis were included. We searched 'osteoarthritis', 'mesenchymal stem cell', 'platelet-rich plasma', and other words in Pubmed, Embase, and Cochrane Library database. The search period encompassed the entire duration of the databases, starting from its inception until April 2024. Two researchers conducted the literature search, extracting data, and evaluating quality as distinct processes. Meta-analysis was carried out using the software RevMan5.3, and the calculation of weighted mean difference (WMD) and 95% confidence interval (CI) were performed using either a fixed-effect model or a random-effects model. Eleven studies were included, comprising 8 randomized controlled trials and 3 cohort studies. A total of 693 individuals participated in the study, of which 394 received intra-articular injections of MSCs (group A) and 299 received intra-articular injections of PRP (group B). The two groups were comparable in the five dimensions of knee injury and osteoarthritis outcome score (KOOS) [pain (WMD: 0.38, 95% CI: -3.62 to 4.38, P > 0.05), symptoms (WMD: -1.48, 95% CI: -5.90 to 2.94, P > 0.05), activities of daily living (ADL, WMD: -2.36, 95% CI: -6.87 to 2.14, P > 0.05), function in sport and recreation (Sport/Rec, WMD: -3.84, 95% CI: -10.60 to 2.92, P > 0.05), knee-related quality of life (QOL, WMD: 0.09, 95% CI: -5.48 to 5.67, P > 0.05)] and Western Ontario and McMaster Universities osteoarthritis index (WOMAC, WMD: 0.47, 95% CI: -3.76 to 4.70, P > 0.05). Compared with group A, the International Knee Documentation Committee Subjective Knee Form (IKDC, WMD: 4.19, 95% CI: 2.57 to 5.82, P < 0.001) score of group B was higher. The short-term effectiveness of intra-articular administration of PRP for managing osteoarthritis is slightly better than that of MSCs. However, because of the limited quantity of incorporated research studies and the potential for bias, requisite in the future are studies of substantial size and superior quality.

THE INFLUENCE OF MESENCHYMAL STEM CELLS ON THE DYNAMICS OF REGULATOR OF ENDOTHELIAL PROLIFERATION EXPRESSIONS IN THE BRAIN STRUCTURES OF RATS WITH EXPERIMENTAL ALZHEIMER-TYPE DEMENTIA

Background. Despite numerous studies, the assessment of the functional state of the vascular endothelium by determining the localization of cells, producers of the endothelial proliferation factor, and measuring the intensity of its production in the brain of rats with dementia of Alzheimer type is of great relevance.&#x0D; Objective: to investigate the impact of mesenchymal stem cells on the functional state of the endothelium of brain vessel in rats with Alzheimer-type dementia by assessing the optical density of brain structures expressing the endothelial proliferation factor.&#x0D; Results. In neurons of the CA1 zone of the hippocampus in gr. SС-14 and in In SС-28, SС-28-MSC, the optical density of cytoplasm marked by endothelial proliferation factor, compared to the control, was 3.6, 1.5, and 2.0 times lower, respectively, and in cortical neurons it did not differ from the control level. After injections of mesenchymal stem cells in all studied groups, there was a decrease in the optical density of labeled factor proliferation of the endothelium of the cytoplasm of cortical neurons and more significantly - in hippocampus neurons (especially in the SС-14-MSC group).&#x0D; Conclusions. In rats with scopolamine-induced dementia of the Alzheimer's type, after 14 days of the "regeneration" period, compared to controls the expression level of vascular factor in hippocampal neurons was significantly lower than that in cortical neurons, which is associated with their greater degree of damage depending on the duration of scopolamine administration, Less active production and more significant reception of endothelial proliferation factor by endotheliocytes was accompanied by a decrease in the optical density of the correspondingly labeled plasma. The introduction of mesenchymal stem cells, probably due to stimulation by the growth factors in them, leads to the activation of the proliferation of the vascular endothelium and a decrease in the synthesis of the own factor of endothelial proliferation.

Subconjunctival autologous muscle-derived mesenchymal stem cell therapy: A novel, minimally invasive approach for treating equine immune-mediated keratitis.

To establish the safety of subconjunctival injections of autologous muscle-derived mesenchymal stem cells (mdMSCs) in healthy horses and to evaluate their effect in four horses (six eyes) with severe chronic equine immune-mediated keratitis (IMMK) that was unresponsive to medical treatments. MdMSCs were cultured from minimally invasive muscle biopsies. In the safety group, four healthy horses received two subconjunctival injections of 2.5 and 5 million cells, respectively, at 1-month interval, to the same eye. Ocular side effects were monitored for 1 month following each injection. In the treatment group, six eyes received four to seven subconjunctival mdMSCs injections (2.5 or 5 million cells per injection) every 4 weeks, approximatively. Medical treatment was discontinued 1 week before and throughout the entire treatment period. A scoring system was used to assess the evolution of the ocular lesions. In the safety group, all horses exhibited mild to moderate chemosis and conjunctival hyperemia at the injection site, lasting 24-48 h. In the treatment group, all eyes initially responded positively to therapy, with a reduction in lesion scores observed after the first injection. Four eyes achieved control of the lesions with repeated injections during the 9.2 months of follow-up. The first subconjunctival injection of mdMSCs resulted in improvement of the ocular lesions. Repeated injections were found to be safe, minimally invasive and showed promise in managing refractory cases of equine IMMK. Further studies are warranted to demonstrate the long-term benefits of these injections and to optimize the therapeutic protocol.